Knockdown of the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Sensitizes Glioma Cells to Hypoxia, Irradiation and Temozolomide

Maurer, Gabriele D.; Heller, Sonja; Wanka, Christina; Rieger, Johannes; Steinbach, Joachim P.

doi:10.3390/ijms20051061

Cited by 16 publications

(16 citation statements)

References 69 publications

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“…The enhancement of glycolysis is a principal characteristic of energy metabolism during glioma development in hypoxic conditions [10]. It has been demonstrated that HIF-1α activation in response to hypoxic stimuli can constitutively promote the expression of glycolytic genes, such as LDHA, GLUT1, HK2 and PKM2, in GBM cells to regulate tumor glycolysis [11,44]. Here, we demonstrated that RLIP76 drives a positive feedback loop to promote the HIF-1α-related signaling pathway by stabilizing HIF-1α, leading to the promotion of hypoxia-induced glycolysis in hypoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

The Positive Feedback Loop Between RLIP76 and HIF-1α Promotes Glycolysis and Tumorigenesis in Glioma Cells Under Hypoxic Conditions

Wang¹,

Zhang²,

Zhang³

et al. 2020

Preprint

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BackgroundHypoxia is intimately associated with increased glycolysis in gliomas, and HIF-1α plays a critical role in this process. Here, we aim to show that RLIP76 is a novel target of HIF-1α and is involved in hypoxia-enhanced glycolysis in glioma cells. MethodsThe human glioma cell lines U87 and U251 were used to explore the interactions of RLIP76-HIF-1α and RLIP76-VHL using Western blot, a Biotin pull-down assay, Immunoprecipitation, and a Chromatin immunoprecipitation assay under hypoxia. U251 cells pretreated with hypoxia were used for tumor xenografts. ResultsRLIP76 is a novel target of HIF-1α and contributes to hypoxia-enhanced glycolysis in glioma cells. HIF-1α-induced RLIP76 can critically regulate the stability of HIF-1α by alleviating VHL-mediated HIF-1α ubiquitination under hypoxia. RLIP76 interacts with HIF-1α and VHL through an RLIP76 GAP-dependent mechanism. The GAP function of RLIP76 regulates its complex formation because of the dependence of RLIP76 GAP on interactions between RLIP76 and these proteins. RLIP76 knockdown results in decreased U251 cell growth after hypoxia pretreatment in vivo. ConclusionsThis study reveals a positive feedback loop between HIF-1α and RLIP76, suggesting that RLIP76 may undergo a complex series of GAP-dependent interactions with HIF-1α and VHL to protect HIF-1α from degradation while promoting glycolysis under hypoxic conditions. We indicate that RLIP76 is crucial for the regulation of hypoxia-enhanced glycolysis and may provide a new gene therapy approach for glioma patients.

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Section: Discussionmentioning

confidence: 99%

The Positive Feedback Loop Between RLIP76 and HIF-1α Promotes Glycolysis and Tumorigenesis in Glioma Cells Under Hypoxic Conditions

Wang¹,

Zhang²,

Zhang³

et al. 2020

Preprint

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“…157 It has also been recognized that HIF-1α transformed glycolysis to pentose phosphate pathway. 158 Mechanically, HIF-1α induced glucose uptake and lactate accumulation, lowered intracellular ATP concentrations, and elevated mitochondrial membrane potential, which was paralleled with the expression level GLUTs, HKⅡ, PKM2, PDK1, and LDH-A. 29 Interestingly, HIF-1α overexpression facilitated the VEGF pathway of vasculogenesis.…”

Section: Interplay Of Transcription Factors In Aerobic Glycolysis Hif-1αmentioning

confidence: 97%

“…34,62 Moreover, growth inhibition was also associated with tumor vessels reduction, enhanced levels of ROS, and autophagic responses. 64,158,159 HIF-1α signaling was also involved in regulating the metabolism, tumor-specific immunity, and tumor growth in glioma. 160 Regarding the effects of chemotherapy and radiotherapy, HIF-1α signaling participated in regulating effectiveness of irradiation and temozolomide of glioma via the glycolytic process.…”

Section: Interplay Of Transcription Factors In Aerobic Glycolysis Hif-1αmentioning

confidence: 99%

“…160 Regarding the effects of chemotherapy and radiotherapy, HIF-1α signaling participated in regulating effectiveness of irradiation and temozolomide of glioma via the glycolytic process. 158,161 Surprisingly, more and more regulators have been detected in the functional activities of HIF-1α in glioma. The hypoxic condition could contribute to the upregulation of HIF-1α via elevating the expression of TIGAR, while prolyl hydroxylation of HIF-1α would happen under normoxic conditions.…”

Section: Interplay Of Transcription Factors In Aerobic Glycolysis Hif-1αmentioning

confidence: 99%

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<p>Emerging Roles and Therapeutic Interventions of Aerobic Glycolysis in Glioma</p>

Han¹,

Shi²,

Cao³

et al. 2020

OTT

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Glioma is the most common type of intracranial malignant tumor, with a great recurrence rate due to its infiltrative growth, treatment resistance, intra-and intertumoral genetic heterogeneity. Recently, accumulating studies have illustrated that activated aerobic glycolysis participated in various cellular and clinical activities of glioma, thus influencing the efficacy of radiotherapy and chemotherapy. However, the glycolytic process is too complicated and ambiguous to serve as a novel therapy for glioma. In this review, we generalized the implication of key enzymes, glucose transporters (GLUTs), signalings and transcription factors in the glycolytic process of glioma. In addition, we summarized therapeutic interventions via the above aspects and discussed promising clinical applications for glioma.

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“…A recent study has reported that the high expression level of PDK1 played an obligate role in the resistance of cisplatin chemotherapy for ovarian cancer [30]. Maurer et al reported that the TP53-induced glycolysis and apoptosis regulator (TIGAR) regulated glycolysis and induced chemoresistance of glioblastoma to temozolomide, which was mediated by HIF-1α [31]. In tumor, cancer cells coexist with multiple non-neoplastic stromal cells, together creating the tumor microenvironment.…”

Section: Glucose and Energy Metabolismmentioning

confidence: 99%

Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Guo

Tan

Chen

et al. 2020

Cancers

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Cancer is a common and complex disease with high incidence and mortality rates, which causes a severe public health problem worldwide. As one of the standard therapeutic approaches for cancer therapy, the prognosis and outcome of chemotherapy are still far from satisfactory due to the severe side effects and increasingly acquired resistance. The development of novel and effective treatment strategies to overcome chemoresistance is urgent for cancer therapy. Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells could rewire metabolic pathways to facilitate tumorigenesis, tumor progression, and metastasis, as well as chemoresistance. The metabolic reprogramming may serve as a promising therapeutic strategy and rekindle the research enthusiasm for overcoming chemoresistance. This review focuses on emerging mechanisms underlying rewired metabolic pathways for cancer chemoresistance in terms of glucose and energy, lipid, amino acid, and nucleotide metabolisms, as well as other related metabolisms. In particular, we highlight the potential of traditional Chinese medicine as a chemosensitizer for cancer chemotherapy from the metabolic perspective. The perspectives of metabolic targeting to chemoresistance are also discussed. In conclusion, the elucidation of the underlying metabolic reprogramming mechanisms by which cancer cells develop chemoresistance and traditional Chinese medicines resensitize chemotherapy would provide us a new insight into developing promising therapeutics and scientific evidence for clinical use of traditional Chinese medicine as a chemosensitizer for cancer therapy.

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Knockdown of the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Sensitizes Glioma Cells to Hypoxia, Irradiation and Temozolomide

Cited by 16 publications

References 69 publications

The Positive Feedback Loop Between RLIP76 and HIF-1α Promotes Glycolysis and Tumorigenesis in Glioma Cells Under Hypoxic Conditions

The Positive Feedback Loop Between RLIP76 and HIF-1α Promotes Glycolysis and Tumorigenesis in Glioma Cells Under Hypoxic Conditions

<p>Emerging Roles and Therapeutic Interventions of Aerobic Glycolysis in Glioma</p>

Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

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